Zinc deficiency in rats is associated with up-regulation of hippocampal NMDA receptor

Prog Neuropsychopharmacol Biol Psychiatry. 2015 Jan 2;56:254-63. doi: 10.1016/j.pnpbp.2014.09.013. Epub 2014 Oct 5.


Rationale: Data indicated that zinc deficiency may contribute to the development of depression; however changes induced by zinc deficiency are not fully described.

Objectives: In the present paper we tested whether the dietary zinc restriction in rats causes alterations in N-methyl-D-aspartate receptor (NMDAR) subunits in brain regions that are relevant to depression.

Methods: Male Sprague Dawley rats were fed a zinc adequate diet (ZnA, 50 mg Zn/kg) or a zinc deficient diet (ZnD, 3 mg Zn/kg) for 4 or 6weeks. Then, the behavior of the rats was examined in the forced swim test, sucrose intake test and social interaction test. Western blot assays were used to study the alterations in NMDAR subunits GluN2A and GluN2B and proteins associated with NMDAR signaling in the hippocampus (Hp) and prefrontal cortex (PFC).

Results: Following 4 or 6 weeks of zinc restriction, behavioral despair, anhedonia and a reduction of social behavior occurred in rats with concomitant increased expression of GluN2A and GluN2B and decreased expression of the PSD-95, p-CREB and BDNF protein levels in the Hp. The up-regulation of GluN2A protein was also found in the PFC, but only after prolonged (6 weeks) zinc deprivation.

Conclusions: The procedure of zinc restriction in rats causes behavioral changes that share some similarities to the pathophysiology of depression. Obtained data indicated that depressive-like behavior induced by zinc deficiency is associated with the changes in NMDAR signaling pathway.

Keywords: Forced swim test; NMDA receptor; Social interaction test; Sucrose intake test; Zinc deficiency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Brain / metabolism*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Disks Large Homolog 4 Protein
  • Food Preferences / psychology
  • Interpersonal Relations
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Membrane Proteins / metabolism
  • Motor Activity / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Sucrose / administration & dosage
  • Swimming / psychology
  • Time Factors
  • Up-Regulation / physiology*
  • Zinc / blood
  • Zinc / deficiency*


  • Brain-Derived Neurotrophic Factor
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Sucrose
  • Zinc
  • N-methyl D-aspartate receptor subtype 2A